Progenitor Stem Model of Dementia And Alzheimer’s Disease

Majid Ali, M.D.

RESTORING OXYGEN, INSULIN, AND GUT MICROBIOME FOR PREVENTION AND TREATMENT OF DEMENTIAS AND ALZHEIMERS DISEASE

140 West End Avenue, New York, NY 10023

212-873-2444

344 Prospect Avenue, Hackensack, New Jersey 07601

201-996-0027

What Is Dementia?

The term dementia is used collectively for a group of neurodegenerative diseases that cause global and progressive deterioration of brain functions, including ability to think, remember, and reason. Other features include difficulties of emotions, communication, language, and motivations. Alzheimer’s diseases is the commest for dementia. The term senility is commonly sued for dementia. Loss of brain substance can generally be documented with brain scanning images, as illustrated below.

1. Not Enough Oxygen

2. Too much insulin

3. Gut Overfermentation

Top Seven for Maladapted Insulin Regulation

4. Overhydrate for at least one to two hours a day, preferably in the morning.

5. Avoid sugar spikes that trigger insulin spikes

6. Love your health fat and proteins, focusing on what you can eat rather than what you cannot.

7. Spend some time in the presence of your larger presence

Breathing Out Slowly

1. Breathe out slowly for spiritual equilibrium

2. Breathe out slowly for grace and gratitude

3. Breathe out slowly for more oxygen

4. Breathe out slowly for health of lungs

5. Breathe out slowly for health of your liver

6. Breathe out slowly for health of you gut

7. Breathe out slowly for health of your brain.

Top Seven for Gut Overfermentation

The Seed-Feed-Weed Path

1. Probiotics

2. Optimal hydration

3. Foods that Do Not Trigger sugar spikes

4. Bowel detox to prevent gut overfermentation

5. Avoid constipation at all costs

6. Castor oil rubs over the stomach and left colon

7. Slow breathing for more oxygen

The Oxygen-Insulin View of Dementia and Alzheimer’s Disease

The author introduced the term “oxygen-insulin view” of insulin homeostasis and the spectrum of insulin dysregulation – hyperinsulinism, metabolic syndromes, gestational diabetes, Type 2 diabetes spectrum (T2D), and diabetic complications – to present a synthesis of his clinical, microscopic, and bioenergetic findings concerning the essential roles of oxygen signaling and insulin homeostasis in the pathobiology of chronic diseases. Specifically, his work extended to the fields of general histopathology,22,23 pathophysiology of aging,24,25 gut immunopathology,26-28 bowel ecology,29,30mitochondrial dysfunction1-3 molecular biology of oxygen,4-8 insulin homeostasis,9-15cancer,31,32 autism,33dysautonnomia,33 and the science and philosophy of holism in health and healing.34 This work led to the recognition that oxygen signaling and insulin signaling are so inextricably intertwined throughout the kaleidoscopic mosaic of human biology that they cannot be considered as discrete entities in any field of study the of the health/dis-ease/diseases continuum.

The author and his colleagues in integrative medicine the clinical oxygen-insulin view, as illustrated by insulin studies in this column, to be very valuable for understanding the scientific underpinnings of diverse disease processes as well as for treating them.35 For optimal long-term clinical outcome, all relevant oxygen and insulin issues for a given patients need to diligently addressed. Treatment of chronic diseases that is confined to pharmacologic agents can be considered neither scientific nor ethical. Readers are invited to closely examine case studies presented in this column. They are drawn from the author’s personal insulin database of over 1100 post-glucose challenge insulin profiles. They can then determine if there is merit to his case for diligence in assessing insulin homeostasis with such laboratory tests. The matters of keeping oxygen homeostasis at the therapeutic center stage for every patient with chronic disease with documentation of clinical outcomes have been covered at length in Darwin and Dysox Triology, the 10th, 11th, and 12th volumes of the Principles and Practice of Integrative Medicine.35-37

To facilitate a critical review of the case studies and highlight core clinical aspects of the profile under consideration, the author offers explanatory notes at www.alidiabetes.org. (For free rapid access, use the search box of the website with the search words: “Townsend Insulin Case Studies”).

Here, the author sees a glaring clinical deficit: a near-complete neglect of relevant oxygen and insulin issues in patient care in doctor offices and clinics in the prevailing medical model in the U.S. To assess the scope of this issue, the author conducted an informal survey of his patients who had seen two or more physicians (primary physician, internists, endocrinologists, diabetologists, and others) during the year prior to visiting me. None of them recalled any visit in which relevant issues of insulin homeostasis or oxygen signaling in were discussed and appropriate tests were performed. Nearly of all them complied with my request to review their prior medical records. I did not find 3-hour post-glucose challenge insulin studies in any patients.

Insulin – The Premium Life Span Hormone

Human life span is put in jeopardy by disruptions of molecular biology of oxygen and insulin homeostasis; life expectancy of an individual is shortened by diminished signaling of the former1-8 as well as by excessive signaling of the latter.9-15 Oxygen is the organizing principle of human biology and orchestrates all aging processes. In service of oxygen, insulin governs the energy economy of the body. Injured cells need more energy for repairing themselves. Glucose is the primary readily useable fuel for ATP energy generation. Insulin activates glucose transporters, drives glucose into the cells, initiates pathways of ATP energy generation, as well as energy utilization for life functions, and regulates energy transformations, producing proteins for cellular structural needs and fats for energy storage.16-21 So it can be rightfully designated as the “master energy hormone” for the life span.

Hyperinsulinism As Body’s Energy Response to Cellular Injury

In the author’s oxygen-insulin view of insulin dysregulation-to-diabetes continuum, hyperinsulinism results from the response of the pancreas to meet increased energy needs of stressed and injured cells anywhere in the body during the repair processes. This perspective does not challenge the established knowledge of dynamics of hyperglycemia and hyperinsulinism, nor does it abandon any of the regulatory roles of pro-insulin and anti-insulin hormones like glucagon, glucagon-like peptides, and others. The explanatory power of the model, however, reaches far beyond the prevailing understanding of insulin functions and their clinical significance.

The inferences drawn from the author’s large personal database and presented here form the scientific basis and rationale for his view that incremental hyperinsulinism develops as a result of growing pancreatic-bioenergetic response for meeting increasing cellular demands for energy, except in cases of ectopic insulin production in hormone-producing neoplasms.29 Additional evidence for this view is drawn from an extensive body of clinical observations concerning improved clinical results of treatment of diverse disorders when hyperinsulinism accompanying them was detected and duly addressed with integrative hyperinsulinism modification plans. It is anticipated that readers, who diligently study the diverse case studies presented here and critically examine the included insulin and glucose data will find them compelling and convincing.

The Crank and Crank-Shaft Model of Insulin Resistance

In one of his 2006 Townsend Letter columns, the author put forth the crank and crank shaft model of insulin resistance, focusing on insulin receptor dysfunction resulting from impaired mitochondrial function.31 In this model, the “crank of insulin” fails to turn the “crank-shaft of insulin receptor” protein embedded in the cell membrane. This occurs when peroxidized lipid, misfolded proteins, and sugar addicts stagnate in cell membranes within accumulations of excess molecular waste and cellular debris as consequences of mitochondrial malfunction and respiratory-to-fermentative shift in ATP generation.32,33 The cell membrane is thickened with grease and glue — so to speak — and the crank-shaft of insulin receptor protein is rusted, turned, and twisted, so rendering the crank of insulin ineffective. Microscopically, such membrane changes can be visualized in some instances, for example, in diabetic nephropathy.34

Hyperinsulism Fans Its Own Fires

As put forth here, hyperinsulinism developing as pancreatic insulin response to increased tissue demands for energy comes at a cost: a “hyper-insulin” state – so to speak – which results from metabolic and non-metabolic insulin overdrive. This insulin state is fattening, fermenting, inflaming, and self-perpetuating. Simply stated, excess insulin begets excess insulinism. From these aspects of pathophysiology of insulin dysfunction and overdrive, abundantly documented by case studies included here and published previously,35,36hyperinsulinism is expected to play central roles in the pathogenesis and progression of most, if not all chronic metabolic, developmental, inflammatory, infectious, autoimmune, degenerative, and malignant diseases.37-41 This, indeed, is observed when insulin homeostasis is assessed in individual patients with appropriate carbohydrate challenges. This is what the author and his colleagues observed in a large survey of hyperinsulinism in a general population in metropolitan New York area. Insulin dysfunction with varying levels of hyperinsulinism was found and documented in all chronic diseases so investigated – acne to dermatitis, psoriasis to sarcoidosis, autism to Alzheimer’s disease, liver steatosis to heart amyloidosis, bronchiectasis to pulmonary fibrosis, lupus to scleroderma, rheumatoid arthritis to Lyme polyarthralgia, interstitial cystitis to recurrent prostatitis, and malignant tumors.42,43

Optimal Insulin Homeostasis

What is optimal insulin homeostasis? Most regrettably, this crucial question has been almost totally ignored in endocrinology, diabetology, bariatrics, and internal medicine. On September 11, 2017, a Google search for optimal insulin homeostasis revealed only seven entries which listed the three words in that order; all of them concerned the author’s own texts. Notably missing were websites of the American Diabetes Association, the European Foundation for the Study of Diabetes, Diabetes Ca (Canada), The American Congress of Obstetricians and Gynecologists, and the World Health Organization.

In the context of healthful aging, the author’s view of the evolutionary bioenergetic ideal of human metabolism is: (1) the lower the blood insulin concentrations following a glucose challenge accompanied by unimpaired glucose tolerance, the greater the efficiency of insulin; (2) the greater the efficiency of insulin, the closer the insulin homeostasis to its ideal; (3) hypoinsulinism by itself is of no clinical consequence since there are no known adverse effects of very low blood insulin concentrations when accompanied by unimpaired glucose tolerance; (4) hyperinsulinism sets the stage of metabolic overdrive in all cellular populations of the body; (5) insulin in excess has hepatic, endothelial, myocardial, neural, ovarian, renal, and other adverse effects; (6) the growth factor roles of insulin intensify and perpetuate inflammatory, autoimmune, and neoplastic processes.

In a survey of insulin homeostasis in 684 patients (506 of them with known T2D, (Table 1) in the general New York metropolitan area, the author and his colleagues reported a prevalence rate of hyperinsulinism in 75.1%.37 A subgroup of twelve participants was designated ‘exceptional insulin homeostasis’ for two reasons: (1) they showed an extremely low fasting insulin value of <2 uIU/mL (mean 14.3 uIU/mL) and peak insulin concentrations <20 uIU/mL accompanied by unimpaired glucose tolerance, and (2) ten of the twelve had no family history of diabetes (parents, siblings, grandparents, children, uncles or aunts), while the mother of the eleventh subject developed T2D in the closing months of her life at age 74 and both parents of the twelfth subject had T2D. This subgroup appears to reflect ideal metabolic efficiency of insulin in the larger evolutionary context.

Table 3 shows the prevalence rates of the categories of optimal insulin homeostasis, and hyperinsulinism of mild, moderate, and severe degrees in 178 survey subjects with Type 2 diabetes. By contrast to the group without Type 2 diabetes, the means of peak glucose levels in this group with Type 2 diabetes do not correlate with means of peak post-glucose insulin concentrations. The fourth category of diabetic insulin depletion in this group indicates varying degrees of pancreatic failure to produce sufficient insulin to override insulin receptor resistance, drive glucose into the cells, and keep glucose in the normal range. The significance of this finding is discussed in the Discussion section of this report.

Table 8. Severe Hyperinsulinism In A 13-Yr-Old With Lupus Erythematosus*

Fasting

½ Hr

1Hr

2Hr

3Hr

Insulin uIU/mL

27.9

362.5

424.0

718.2

571.7

Glucose mg/mL (mmol/L)

70 (3.88)

140 (7.77)

157 (8.71)

150 (8.33)

111 (6.16)

Insulin and Glucose Profiles Obtained After Four Months of Robust Integrative Therapies

Insulin uIU/mL

7.2

125.1

238.5

208.0

132.0

Glucose mg/mL (mmol/L)

81 (4.49)

154 (8.54)

181 (10.04)

130 (7.21)

97 (5.38)

*The Patient, A 13-Yr-Old Girl With a History of Three Hospitalizations In One Year for Systemic Lupus Erythematosus, Recurrent Pneumonia, Thrombocytopenia, and Severe Optic Neuritis Resulting In Complete Loss of Vision In Right Eye. The Peak Insulin Fell from 718 to 238.5 In Four Months of Robust Integrative Treatment.

Table 3 shows the prevalence rates of the categories of optimal insulin homeostasis, and hyperinsulinism of mild, moderate, and severe degrees in 178 survey subjects with Type 2 diabetes. By contrast to the group without Type 2 diabetes, the means of peak glucose levels in this group with Type 2 diabetes do not correlate with means of peak post-glucose insulin concentrations. The fourth category of diabetic insulin depletion in this group indicates varying degrees of pancreatic failure to produce sufficient insulin to override insulin receptor resistance, drive glucose into the cells, and keep glucose in the normal range. The significance of this finding is discussed in the Discussion section of this report.

Table 8. Severe Hyperinsulinism In A 13-Yr-Old With Lupus Erythematosus*

Fasting

½ Hr

1Hr

2Hr

3Hr

Insulin uIU/mL

27.9

362.5

424.0

718.2

571.7

Glucose mg/mL (mmol/L)

70 (3.88)

140 (7.77)

157 (8.71)

150 (8.33)

111 (6.16)

Insulin and Glucose Profiles Obtained After Four Months of Robust Integrative Therapies

Insulin uIU/mL

7.2

125.1

238.5

208.0

132.0

Glucose mg/mL (mmol/L)

81 (4.49)

154 (8.54)

181 (10.04)

130 (7.21)

97 (5.38)

*The Patient, A 13-Yr-Old Girl With a History of Three Hospitalizations In One Year for Systemic Lupus Erythematosus, Recurrent Pneumonia, Thrombocytopenia, and Severe Optic Neuritis Resulting In Complete Loss of Vision In Right Eye. The Peak Insulin Fell from 718 to 238.5 In Four Months of Robust Integrative Treatment.